tbuckley/cabot-search huggingface dataset:
KRAS mutant–driven SUMOylation controls extracellular vesicle transmission to trigger lymphangiogenesis in pancreatic cancer
Authors: Yuming Luo, Zhihua Li, Yao Kong, Wang He, Hanhao Zheng, Mingjie An, Yan Lin, Dingwen Zhang, Jiabin Yang, Yue Zhao, Changhao Chen, Rufu Chen
Journal: Journal of Clinical Investigation (2022)

Lymph node (LN) metastasis occurs frequently in pancreatic ductal adenocarcinoma (PDAC) and predicts poor prognosis for patients. The KRASG12D mutation confers an aggressive PDAC phenotype that is susceptible to lymphatic dissemination. However, the regulatory mechanism underlying KRASG12D mutation-driven LN metastasis in PDAC remains unclear. Herein, we found that PDAC with the KRASG12D mutation (KRASG12D PDAC) sustained extracellular vesicle-mediated (EV-mediated) transmission of heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1) in a SUMOylation-dependent manner and promoted lymphangiogenesis and LN metastasis in vitro and in vivo. Mechanistically, hnRNPA1 bound with SUMO2 at the lysine 113 residue via KRASG12D-induced hyperactivation of SUMOylation, which enabled its interaction with TSG101 to enhance hnRNPA1 packaging and transmission via EVs. Subsequently, SUMOylation induced EV-packaged-hnRNPA1 anchoring to the adenylate- and uridylate-rich elements of PROX1 in lymphatic endothelial cells, thus stabilizing PROX1 mRNA. Importantly, impeding SUMOylation of EV-packaged hnRNPA1 dramatically inhibited LN metastasis of KRASG12D PDAC in a genetically engineered KrasG12D/+ Trp53R172H/+ Pdx-1-Cre (KPC) mouse model. Our findings highlight the mechanism by which KRAS mutant-driven SUMOylation triggers EV-packaged hnRNPA1 transmission to promote lymphangiogenesis and LN metastasis, shedding light on the potential application of hnRNPA1 as a therapeutic target in patients with KRASG12D PDAC.
Association of Psychiatric Services Referral and Attendance Following Treatment for Deliberate Self-harm With Prospective Mortality in Norwegian Patients
Authors: Ping Qin, Barbara Stanley, Ingrid Melle, Lars Mehlum
Journal: JAMA Psychiatry (2022)

Psychiatric care following somatic treatment for deliberate self-harm (DSH) is pivotal in patients' lives both in the short and long term, but evidence to guide such care is limited.To examine follow-up psychiatric care for patients treated for DSH (ie, intentional self-injury or self-poisoning, irrespective of motivation) at hospital emergency departments and to assess the association of psychiatric referral and treatment attendance with risk of subsequent mortality in these patients.Retrospective data from several Norwegian registries were interlinked to follow up a national cohort of all patients with hospital-treated DSH for up to 11 years from 2008 through 2018. Data were analyzed from March to October 2021.Socioeconomic characteristics, psychiatric history, and clinical features of DSH.Referral to psychiatric services, attendance in psychiatric treatment, and prospective mortality were the 3-stage outcomes during follow-up. Logistic regression with odds ratios and cause-specific survival analysis with hazard ratios were used to examine associations between exposures and outcomes.The study identified 43 153 patients (24 286 [56.3%] female; median [IQR] age at index DSH, 39.0 [23.0-56.0] years) involving 69 569 DSH episodes. Of these patients, 6762 (15.7%) were referred to psychiatric services after somatic treatment for DSH, and 22 008 patients (51.0%) attended psychiatric treatment within 3 months of discharge following somatic treatment for DSH. Prior psychiatric history and psychiatric disorders comorbid with DSH were associated with both referral to and attendance in psychiatric care. During follow-up, 7041 patients died by suicide (n = 911) or other causes (n = 6130). While suicide risk was associated with male sex, age 35 to 64 years, and particularly prior and coexisting psychopathologies, other-cause mortality was associated with age 65 years and older and socioeconomic disadvantage. Patients with psychiatric referrals generally had an increased risk of suicide, but the risk was particularly high among patients who received a referral but did not subsequently attend psychiatric treatment (adjusted hazard ratio, 3.07; 95% CI, 2.28-4.12). The observed association was more pronounced during the first years of follow-up and in patients aged 10 to 34 years or 35 to 64 years and those with a clear intent of self-harm.This national cohort study found an association between psychiatric care attendance following treatment for DSH and prospective mortality, highlighting the importance of patient engagement in psychiatric treatment.
Identity and psychological distress in alopecia areata
Authors: Nigel Hunt
Journal: British Journal of Dermatology (2022)

Linked Article: Macbeth et al. Br J Dermatol 2022; https://doi.org/10.1111/bjd.21055 In this issue of the BJD, Macbeth and her seven coauthors provide a timely article regarding mental health conditions associated with alopecia areata (AA).1 In the past, this area has been neglected by many dermatologists and others when considering the treatment of AA, a problem we discussed nearly 20 years ago.2 Focusing specifically on depression and anxiety, as these are probably the most likely mental health concomitants of AA, this large-scale study found that both conditions are more common among people diagnosed with AA than among controls. This is not a surprising finding. Hair is of fundamental importance in projecting the self-image, and a dramatic change in appearance can profoundly affect the way people see themselves.3 In this sense AA is similar to other forms of disfigurement. We have long acknowledged the importance of the psychosocial aspects of, for example, facial disfigurement, but hair has similarities because it can be just as important for self-esteem as any other part of appearance. Many women (in particular) see their hair as their ‘crowning glory’, so the loss of hair can be particularly distressful for women.4 Macbeth et al. did not compare sex differences. It would have been helpful to see whether previous findings regarding sex differences are repeated, or whether cultural change has altered the pattern of psychosocial problems experienced by men and women. One important finding from the study of Macbeth et al. is not just that people with AA were more likely to experience depression and anxiety, but that they were also more likely to be issued time off work certificates and be recorded as unemployed. We know that hair loss can affect whether people take part in social activities such as sport5 or sexual activity,6 so this adds to the evidence regarding the inability of many people with AA to take part in normal social activities, presumably directly because of their hair loss. The authors do recognize some of the limitations of their study. In addition to this, one problem may be the focus on medications as the main indicators of depression and anxiety. While this provides a reasonable measure of the classification of depression and anxiety, it is not without its faults. Many people experiencing symptoms of depression and anxiety do not go to their doctor and obtain medication. On the other hand, some people may be prescribed medication without a full assessment of their mental health. These issues are not likely to change the overall picture that many people with AA experience psychosocial problems. Perhaps the most important point made by Macbeth et al. is that people with AA who experience psychological distress should be provided with appropriate support, and that we need to develop and test appropriate psychological therapies for use with AA. Psychologists do have appropriate therapies available. We must recognize the need for these among people with AA.
Plasticity Enables Cooperation among Heterogeneous Cancer Cell Populations to Support Metastatic Fitness
Authors: Valerie S. LeBleu
Journal: Cancer Research (2022)

The invasive progression of cancer known as metastasis remains strongly associated with morbidity and lethality. New meaningful therapeutic interventions could be derived from a better understanding of the underlying processes driving cancer cell seeding and proliferation at secondary sites. Emerging findings regarding the heterogeneity of cancer cells observed in metastases have led us to revisit concepts surrounding metastatic fitness. Novel model systems to study the markers of cancer stem cell plasticity and their evolution during metastatic growth have uncovered that dynamic and heterogeneous cancer cell populations are observed during metastatic disease progression. Heinz and colleagues studied the heterogeneity of colorectal carcinomas, where primary tumors evolve alongside an epithelium well characterized for its self-renewing stem cell population. Their work revealed a functional dynamic interplay in the organization of the metastatic lesions as they transition from stagnating to expanding nodules, wherein the heterogeneous mixture of cancer cell stem cells with more differentiated cancer cells is essential for metastatic outgrowth. Their work supports that dynamic YAP signaling enables the growth-permissive heterogeneous composition of the metastatic nodule, in contrast with growth-restricted homogeneous compositions. See related article by Heinz et al., p. 1953.
Matt Morgan: The death of the dictaphone
Authors: Matt Morgan
Journal: BMJ (2022)

The death of the dictaphone Matt Morgan consultant in intensive care medicineThe clicking of dictaphones starting, stopping, and rewinding used to echo around busy outpatient clinics.Tiny cassette tapes were scattered over the desks for medical secretaries to decipher and translate garbled sounds into organised words.These secretaries were the conductors of the hospital-coordinating, organising, typing, and supporting.They still are.
Obstructive Sleep Apnea and Hypertension with Longitudinal Amyloid-β Burden and Cognitive Changes
Authors: Omonigho M. Bubu, Sonya S. Kaur, Alfred K. Mbah, Ogie Q. Umasabor-Bubu, Jaime Ramos Cejudo, Ludovic Debure, Anna E. Mullins, Ankit Parekh, Korey Kam, Zainab T. Osakwe, Ellita T. Williams, Arlener D. Turner, Lidia Glodzik, David M. Rapoport, Gbenga Ogedegbe, Els Fieremans, Mony J. de Leon, Indu Ayappa, Girardin Jean-Louis, Arjun V. Masurkar, Andrew W. Varga, Ricardo S. Osorio
Journal: American Journal of Respiratory and Critical Care Medicine (2022)

"Obstructive Sleep Apnea and Hypertension with Longitudinal Amyloid-β Burden and Cognitive Changes." American Journal of Respiratory and Critical Care Medicine, 206(5), pp. 632–636
A Randomized Controlled Trial of Statins to Reduce Inflammation in Unruptured Cerebral Aneurysms
Authors: Huibin Kang, De-Cai Tian, Xinjian Yang, Yisen Zhang, Wenqiang Li, Binbin Sui, Yunyun Duan, Ying Zhang, Jian Liu, Kun Wang, Anxin Wang, Mirzat Turhon, Mahmud Mossa-Basha, Michael R. Levitt, David Hasan, Chengcheng Zhu
Journal: JACC. Cardiovascular imaging (2022)
Association of Gabapentin Use With Pain Control and Feeding Tube Placement Among Patients With Head and Neck Cancer Receiving Chemoradiotherapy
Authors: Sung Jun Ma, Katy Wang, Austin J. Iovoli, Kristopher Attwood, Gregory Hermann, Mark Farrugia, Anurag K. Singh
Journal: JAMA Network Open (2022)

This comparative-effectiveness study uses data from 2 clinical trials to evaluate whether the use of gabapentin for pain management is associated with less opioid use and feeding tube placement among adult patients with head and neck cancer receiving chemoradiotherapy.
Single-cell analysis implicates TH17-to-TH2 cell plasticity in the pathogenesis of palmoplantar pustulosis
Authors: Daniel McCluskey, Natashia Benzian-Olsson, Satveer K. Mahil, Niina Karoliina Hassi, Christian T. Wohnhaas, A. David Burden, Christopher E.M. Griffiths, John R. Ingram, Nick J. Levell, Richard Parslew, Andrew E. Pink, Nick J. Reynolds, Richard B. Warren, Sudha Visvanathan, Patrick Baum, Jonathan N. Barker, Catherine H. Smith, Francesca Capon
Journal: Journal of Allergy and Clinical Immunology (2022)

Palmoplantar pustulosis (PPP) is a severe inflammatory skin disorder characterized by eruptions of painful, neutrophil-filled pustules on the palms and soles. Although PPP has a profound effect on quality of life, it remains poorly understood and notoriously difficult to treat.We sought to investigate the immune pathways that underlie the pathogenesis of PPP.We applied bulk and single-cell RNA sequencing (RNA-Seq) methods to the analysis of skin biopsy samples and peripheral blood mononuclear cells. We validated our results by flow cytometry and immune fluorescence microscopy RESULTS: Bulk RNA-Seq of patient skin detected an unexpected signature of T-cell activation, with a significant overexpression of several TH2 genes typically upregulated in atopic dermatitis. To further explore these findings, we carried out single-cell RNA-Seq in peripheral blood mononuclear cells of healthy and affected individuals. Memory CD4+ T cells of PPP patients were skewed toward a TH17 phenotype, a phenomenon that was particularly significant among cutaneous lymphocyte-associated antigen-positive skin-homing cells. We also identified a subset of memory CD4+ T cells that expressed both TH17 (KLRB1/CD161) and TH2 (GATA3) markers, with pseudotime analysis suggesting that the population was the result of TH17 to TH2 plasticity. Interestingly, the GATA3+/CD161+ cells were overrepresented among the peripheral blood mononuclear cells of affected individuals, both in the single-cell RNA-Seq data set and in independent flow cytometry experiments. Dual-positive cells were also detected in patient skin by immune fluorescence microscopy.PPP is associated with complex T-cell activation patterns and may explain why biologic drugs that target individual T helper cell populations have shown limited therapeutic efficacy.
Lung Microbiota and Metabolites Collectively Associate with Clinical Outcomes in Milder Stage Chronic Obstructive Pulmonary Disease
Authors: Siddharth S. Madapoosi, Charmion Cruickshank-Quinn, Kristopher Opron, John R. Erb-Downward, Lesa A. Begley, Gen Li, Igor Barjaktarevic, R. Graham Barr, Alejandro P. Comellas, David J. Couper, Christopher B. Cooper, Christine M. Freeman, MeiLan K. Han, Robert J. Kaner, Wassim Labaki, Fernando J. Martinez, Victor E. Ortega, Stephen P. Peters, Robert Paine, Prescott Woodruff, Jeffrey L. Curtis, Gary B. Huffnagle, Kathleen A. Stringer, Russell P. Bowler, Charles R. Esther, Nichole Reisdorph, Yvonne J. Huang, Neil E. Alexis, Wayne H. Anderson, Mehrdad Arjomandi, Lori A. Bateman, Surya P. Bhatt, Eugene R. Bleecker, Richard C. Boucher, Stephanie A. Christenson, Gerard J. Criner, Ronald G. Crystal, Claire M. Doerschuk, Mark T. Dransfield, Brad Drummond, Craig Galban, Nadia N. Hansel, Annette T. Hastie, Eric A. Hoffman, Richard E. Kanner, Eric C. Kleerup, Jerry A. Krishnan, Lisa M. LaVange, Stephen C. Lazarus, Deborah A. Meyers, Wendy C. Moore, John D. Newell, Laura Paulin, Cheryl Pirozzi, Nirupama Putcha, Elizabeth C. Oelsner, Wanda K. O’Neal, Sanjeev Raman, Stephen I. Rennard, Donald P. Tashkin, J. Michael Wells, Robert A. Wise
Journal: American Journal of Respiratory and Critical Care Medicine (2022)

Chronic obstructive pulmonary disease (COPD) is variable in its development. Lung microbiota and metabolites collectively may impact COPD pathophysiology, but relationships to clinical outcomes in milder disease are unclear.
Treatment of Hypersensitivity Pneumonitis (HP)
Authors: Brandon Janssen, Samuel Epstein, Diana Gomez-Manjarres, Divya C. Patel
Journal: American Journal of Respiratory and Critical Care Medicine (2022)

"Treatment of Hypersensitivity Pneumonitis (HP)." American Journal of Respiratory and Critical Care Medicine, 205(10), pp. P20–P21
Multiancestral polygenic risk score for pediatric asthma
Authors: Bahram Namjou, Michael Lape, Edyta Malolepsza, Stanley B. DeVore, Matthew T. Weirauch, Ozan Dikilitas, Gail P. Jarvik, Krzysztof Kiryluk, Iftikhar J. Kullo, Cong Liu, Yuan Luo, Benjamin A. Satterfield, Jordan W. Smoller, Theresa L. Walunas, John Connolly, Patrick Sleiman, Tesfaye B. Mersha, Frank D. Mentch, Hakon Hakonarson, Cynthia A. Prows, Jocelyn M. Biagini, Gurjit K. Khurana Hershey, Lisa J. Martin, Leah Kottyan
Journal: Journal of Allergy and Clinical Immunology (2022)
Athletes With Cardiovascular Disease and Competitive Sports Eligibility
Authors: Jonathan H. Kim, Neal W. Dickert
Journal: JAMA Cardiology (2022)

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Predicting Mortality for Patients Eligible for Extracorporeal Membrane Oxygenation for COVID-19
Authors: Whitney D. Gannon, John W. Stokes, Wu Gong, Christopher J. Lindsell, Joseph E. Tonna, Matthew Bacchetta, Todd W. Rice, Matthew W. Semler, Jonathan D. Casey
Journal: American Journal of Respiratory and Critical Care Medicine (2022)
Abstract A029: Identification of tumor microenvironment components in patient-derived pancreatic ductal adenocarcinoma organoids
Authors: Mei Gao, Charles J. Bailey, Megan M. Harper, Michael J. Cavnar, Prakash Pandalai, Shadi A. Qasem, Joseph Kim
Journal: Cancer Research (2022)

Abstract Background: Pancreatic ductal adenocarcinoma (PDAC) is highly drug resistant with no change in therapeutic approach for the last decade. The PDAC tumor microenvironment (TME) is highly desmoplastic and associated with altered treatment response. Our group previously identified 9 distinct cell types in human PDAC tumors using single-cell RNA-sequencing, demonstrating a diverse TME. However, the TME of in vitro organoid PDAC models remains underexplored. We initiated characterization of the TME from PDAC patient derived organoids (PDOs) to establish a working model for accurate drug sensitivity testing. Methods: We performed immunofluorescence (IF) staining on whole-mount early passage (&amp;lt;P4) PDO lines and corresponding paraffin-embedded primary PDAC specimens to evaluate for activated cancer-associated fibroblasts (CAFs) using antibodies against α-smooth muscle actin (α-SMA) and fibroblast activated protein (FAP); and to evaluate for T-regulatory (Treg) cells with antibodies against interleukin-2 receptor α (IL-2Rα) and forkhead box protein P3 (FOXP3). Results: CAFs promote an immunosuppressive TME in PDAC and have recently been subclassified into inflammatory fibroblasts and myofibroblasts, which can both restrain and promote tumor progression. In this study, we identified three distinct subtypes of CAFs in PDOs, which are consistent with the subtypes found in matched clinical tumor specimens: α-SMA+, which has been reported to be indicative of pancreatic stellate cell activation and associated with increased desmoplasia; FAP+, which influences cancer cell motility, invasion, and cycle progression, extracellular matrix deposition, and angiogenesis within the TME; and α-SMA+/FAP+, which is a myofibroblast subtype. We additionally identified Treg populations in PDOs with peripheral IL-2Rα and central FOXP3 expression in the organoid spheres. Tregs have previously been shown to be overexpressed in the PDAC TME, making this finding clinically relevant. Conclusions: In this preliminary study, we show that PDAC PDOs demonstrate TME components that mirror primary tumor specimens, including CAFs and Tregs. The demonstration of a tumor-matched, immunocompetent TME in PDAC PDOs provides a more clinically relevant in vitro tumor model for patient-matched drug sensitivity testing. Citation Format: Mei Gao, Charles J. Bailey, Megan M. Harper, Michael J. Cavnar, Prakash Pandalai, Shadi A. Qasem, Joseph Kim. Identification of tumor microenvironment components in patient-derived pancreatic ductal adenocarcinoma organoids [abstract]. In: Proceedings of the AACR Special Conference on the Evolutionary Dynamics in Carcinogenesis and Response to Therapy; 2022 Mar 14-17. Philadelphia (PA): AACR; Cancer Res 2022;82(10 Suppl):Abstract nr A029.
Development of the Endoscopic Pouch Score for Assessment of Inflammatory Conditions of the Pouch
Authors: Edward L. Barnes, Millie D. Long, Laura Raffals, Kim Isaacs, Ryan W. Stidham, Hans H. Herfarth, Parakkal Deepak, Poonam Beniwal-Patel, Maia Kayal, Marla Dubinsky, Shannon Chang, Peter D.R. Higgins, Jennifer I. Barr, Yue Jiang, Raymond K. Cross
Journal: Clinical Gastroenterology and Hepatology (2022)
Biomimetic AgNPs@antimicrobial peptide/silk fibroin coating for infection-trigger antibacterial capability and enhanced osseointegration
Authors: Wenhao Zhou, Tian Bai, Lan Wang, Yan Cheng, Dandan Xia, Sen Yu, Yufeng Zheng
Journal: Bioactive Materials (2022)

Endowing implant surfaces with combined antibacterial and osteogenic properties by drug-loaded coatings has made great strides, but how to achieve the combined excellence of infection-triggered bactericidal and in vivo-proven osteogenic activities without causing bacterial resistance still remains a formidable challenge. Herein, antimicrobial peptides (AMPs) with osteogenic fragments were designed and complexed on the surface of silver nanoparticle (AgNP) through hydrogen bonding, and the collagen structure-bionic silk fibroin (SF) was applied to carry AgNPs@ AMPs to achieve infection-triggered antibacterial and osteointegration. As verified by TEM, AMPs contributed to the dispersion and size-regulation of AgNPs, with a particle size of about 20 nm, and a clear protein corona structure was observed on the particle surface. The release curve of silver ion displayed that the SF-based coating owned sensitive pH-responsive properties. In the antibacterial test against S.aureus for up to 21 days, the antibacterial rate had always remained above 99%. Meanwhile, the underlying mechanism was revealed, originating from the destruction of the bacterial cell membranes and ROS generation. The SF-based coating was conducive to the adhesion, diffusion, and proliferation of bone marrow stem cells (BMSCs) on the surface, and promoted the expression of osteogenic genes and collagen secretion. The in vivo implantation results showed that compared with the untreated Ti implants, SF-based coating enhanced osseointegration at week 4 and 8. Overall, the AgNPs@AMPs-loaded SF-based coating presented the ability to synergistically inhibit bacteria and promote osseointegration, possessing tremendous potential application prospects in bone defects and related-infection treatments.